Despite 20 years of outstanding scientific accomplishments in the field of HIV research, from the identification of HIV as the causative agent for AIDS to the development of effective antiretroviral drugs, the AIDS epidemic remains a formidable global health challenge. Most anti-HIV medications available to date belong to two classes of inhibitors that target viral enzymes: reverse transcriptase and protease. Although highly active antiretroviral therapy (HAART) has been effective in reducing the mortality and morbidity in recent years, issues such as long term side effects, customized and complicated dosing regimens and, more seriously, the emergence of multidrug-resistant viral variants, still remain. These challenges have prompted the search for new treatment agents beyond viral reverse transcriptase and protease inhibitors and the discovery of new classes of potent and less-toxic anti-HIV-1 drugs with a different mechanism of action is needed.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and they also play a role in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Chemokines are small 70 to 80 amino acid proteins with well-characterized three-dimensional structures, usually stabilized by two disulfide bridges. They are divided into four families on the basis of pattern of conserved cysteine residues. Chemokine receptors have been designated such as, CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, and CXCR4 and therefore agents which modulate these receptors may be useful in the prevention and treatment of diseases as mentioned above.
For a review of possible applications of chemokines and chemokine receptor blockers see Riberio and Horuk, “The Clinical Potential of Chemokine Receptor Antagonists”, Pharmacology and Therapeutics 107 (2005) p 44-58.
One of them, the C—C chemokines family, includes potent chemoattractants of monocytes and lymphocytes such as RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin, MIP-1α and MIP-1β (Macrophage Inflammatory Proteins) and human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3). More specifically, C—C chemokine receptor 5 (CCR5), a β-chemokine receptor with a seven-transmembrane-protein structure, was found to serve as a coreceptor for non-syncytium-inducing or macrophage-tropic HIV-1 (R5 viruses). It was also established that CCR5 is the principal chemokine receptor required for the entry of HIV into the cell during primary infection. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. It would therefore be useful to provide novel compounds which are modulators of chemokine receptor activity.
PCT applications PCT/CA2005/001877 or PCT/CA2005/001878 disclose certain spirotropane compounds that are useful for the prevention or treatment of HIV infections, as well as diseases associated with the modulation of CCR5 chemokine receptor activity.
Compounds of the present invention are generically disclosed in PCT applications PCT/CA2005/001877 or PCT/CA2005/001878 but none is specifically exemplified therein.